Recent concerns over the use of smallpox (variola) virus as a biological weapon have prompted renewed interest in development of small molecule therapeutics that target variola virus replication. Variola virus is highly transmissible and causes severe disease in humans resulting in high mortality rates. Currently, there is no FDA-approved drug for the prevention or treatment of smallpox. The overall goal of our smallpox antiviral program is to advance through FDA approval at least one small molecule antiviral drug for treatment and prevention of smallpox that will be safe, effective and orally administered as a capsule, tablet or liquid for treatment, post-exposure prophylactic and prophylactic applications. The objective of this SBIR Phase II smallpox virus project is to advance the early stage variola virus-specific antiviral compounds discovered during our SBIR Phase I work into chemical optimization, through animal efficacy and IND-enabling toxicology, to clinical development stage candidates for which we will submit IND applications. Human safety and pharmacokinetic studies are beyond the scope of the Phase II work plan. At the end of this 3-year SBIR Phase II Smallpox program, we anticipate that we will submit at least one IND application for an antiviral drug candidate for the treatment and prevention of smallpox and identify at least one additional smallpox preclinical candidate. The availability of smallpox virus-specific antiviral drugs will address national and global security needs by acting as significant deterrents and defenses against use of smallpox virus in potential bioterrorist attacks. Antiviral drugs may be readily stockpiled and rapidly deployed in the event of a smallpox virus outbreak. Since antiviral drugs are easily administered (oral pill or liquid) and exert their antiviral effect rapidly (within hours of administration), they will serve to effectively treat diseased patients, protect those suspected of being exposed to the pathogen (post-exposure prophylaxis), and assist in the timely containment of the outbreak.